Pulmonary hypertension (PH) is a general term for pathological conditions that manifest a rise in pulmonary arterial pressure. A cause thereof has not yet been identified, though it is known that there are pulmonary hypertensions induced by various causes such as pulmonary hypertension associated with a pre-existing disease including pulmonary diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), interstitial pneumonia, and pulmonary emphysema; left heart diseases such as left ventricular failure and valvular disease; systemic diseases such as sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, and vasculitis; and primary pulmonary arterial hypertension which originates from pulmonary arteries, etc. (Non Patent Literature 1).
Pulmonary hypertension develops due to a rise in pulmonary arterial pressure resulting from increased vascular resistance in pulmonary arterioles, etc. Pulmonary hypertension is diagnosed when an average pulmonary arterial pressure is 25 mmHg or higher. In chronic pulmonary hypertension, the overload of the right ventricle and right-ventricular failure, which result from progression of pulmonary peripheral vessels remodeling and angiostenosis due to a high pulmonary arterial pressure, cause clinical symptoms such as systemic congestion, breathlessness, easy fatigability, reduced labor power, fainting episodes, ascites, and cyanosis.
The treatment of pulmonary hypertension is performed by vasodilatory therapy using calcium antagonists, prostaglandin I2 analog formulations, nitric oxide (NO) gas, or the like, oxygen therapy, measures to prevent heart failure, anticoagulation therapy with warfarin or the like, and surgical treatment such as lung transplantation.
A plurality of animal models are known for the pathological analysis of pulmonary hypertension or explore therapeutic methods (Non Patent Literature 2). Particularly, a rodent model given interleukin-33 (IL-33) (Patent Literature 1), a rodent model with a particular molecule knocked out (Non Patent Literature 3), and a transgenic rodent model rather caused to express a particular molecule are known for the analysis of the molecular mechanism and are under pathological analysis.
Among others, it is known in the analysis of adiponectin-knockout mice that OVA-induced pulmonary hypertension is caused, leading to vascular remodeling and increased eosinophil infiltration (Non Patent Literature 3). Also, it is known that in the PH models, an anti-interleukin-5 (IL-5) ligand antibody decreases eosinophil infiltration and vascular wall thickening (Non Patent Literature 4).
Therapeutic agents targeting IL-5-IL-5R have been developed in the field of asthma. Anti-IL-5 humanized antibodies mepolizumab (IgG1) and reslizumab (IgG4/κ) and an anti-IL-5Rα antibody benralizumab (MEDI-563) are known (Patent Literatures 2 and 3 and Non Patent Literatures 5 and 6).